The specific aims of this proposal are to use a newly developed intracellular energy delivery technique to enhance resuscitation, and to study the relationship between tissue high-energy phosphate supplementation and tissue necrosis and apoptosis during hemorrhagic shock. In most western countries, trauma/hemorrhage is the leading cause of death up to the age of 40. The most common consequence of severe trauma and hemorrhage is shock, which is a hypovolemic condition in which oxygen delivery to the body is inadequate for the generation of the adenosine triphosphate (ATP) and adenosine diphosphate (ADP) necessary to maintain the function and structural integrity of tissues. Treatment strategies for shock have changed very little in the past half century and the incidence of mortality and morbidity remains very high. Depletion of high-energy phosphates during hemorrhagic shock was described decades ago, and direct administration of free Mg-ATP was reported to increase tissue ATP concentrations, tissue and mitochondrial Mg levels, and cellular functions by some authors. However, this approach is controversial, not only because the protective effects cannot always be duplicated by other scientists, but also because the half life of ATP is very short in the blood circulation-less than 40 seconds. Furthermore, it i well known that highly charged molecules like ATP do not normally cross the cell membrane. We have developed a technique for intracellular Mg-ATP delivery (named ATP- vesicles or VitaSolTM). Preliminary results have indicated a very promising effect in several models of tissue hypoxia and ischemia, including shock. Our hypothesis is that the replenishment of intracellular ATP levels alleviates or eliminates many of the detrimental effects caused by hemorrhagic shock, thereby increasing survival time. This Phase I proposal has two aims: 1) To establish the effect of VitaSolTM treatment on hemorrhagic shock; and 2) To investigate the relationship between tissue high- energy phosphate contents and necrosis and apoptosis during hemorrhagic shock, and the effect of VitaSolTM treatment on these changes. These studies have not been performed in the past. The success of this project will likely provide a totally new therapeutic approach for treatment of severe trauma and shock. Further study of this new energy delivery technique may also benefit various clinical conditions, such as coronary heart disease, stroke, spinal cord injury, cardiopulmonary bypass, organ transplant, chronic wounds, and many other conditions where ischemia is involved. The potential impact on medicine is high. PUBLIC HEALTH RELEVANCE: Trauma/hemorrhage is the leading cause of death up to the age of 40 in most western countries, but no effective treatment has been developed and mortality remains very high. This proposal is to use our newly developed intracellular energy delivery technique to enhance resuscitation in hemorrhagic shock. The success of this project will likely have a major impact on medicine.